Method for preparing azetidinone compound and intermediate of azetidinone compound

ABSTRACT

Disclosed is a new method for preparing an azetidinone compound represented by formula (I). The carboxylic ketoester represented by formula (II) serves as the raw material and is subjected to Grignard addition, stereoselective dehydration, ester group reduction, hydroxyl group protection, addition with imine after condensation with a chiral auxiliary, cyclization and deprotection to obtain the compound represented by formula (I). The present invention has advantages of easily available raw material, a few synthetic steps, simple operation, high yield, good stereoselectivity and low cost, and can be used for industrial production.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 15/317,297 filed on Dec. 8, 2016, which is a national phase entryunder 35 U.S.C. § 371 of International Application No.PCT/CN2015/080893, filed Jun. 5, 2015, which claims priority fromChinese Patent Application No. 201410251262.5, filed Jun. 9, 2014, allof which are hereby incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to the field of chemistry, especially to anew preparation method of a cholesterol absorption inhibiting agent, thecompound of formula (I), i.e.(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybut-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one and the synthesized intermediate thereof.

TECHNICAL BACKGROUND

In western countries, coronary atherosclerotic heart disease (coronaryheart disease) is the leading cause of death, and cholesterol is one ofthe risk factors that cause this disease. At present, there are twokinds of medicines that are used to the reduction of plasma cholesterollevels. One is Statins, which is a HMG-CoA reductase inhibitor, and caneffectively inhibit the biosynthesis of cholesterol in vivo. Anotherkind of role is to prevent the absorption of cholesterol from smallintestine, and Ezetimibe is a common cholesterol absorption inhibitor.US patent (U.S. Pat. No. 5,846,966) describes Ezetimibe, the chemicalstructure is as follows:

The side chain at the 3-position carbon of the azetidinone is a chiralbenzyl alcohol, and the chiral carbon is of S configuration. Thestructure-activity relationship shows that the pharmacodynamicproperties of S configuration is better than the R configuration, whichindicates that the stereochemistry of the carbon of the benzyl is veryimportant.

WO2011/017907 discloses a new kind of azetidinone compounds, which canalso effectively inhibit the absorption of cholesterol, but the sidechain on the 3-carbon of the azetidinone is not a chiral benzyl alcoholbut an achiral allyl alcohol, and the pharmacodynamic properties of thedouble bonds of Z configuration is much better than the double bonds ofE configuration. Among this kind of compounds, the chemical structure ofthe compound with the best pharmacodynamic properties, i.e.(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybut-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one is as follows:

Because the synthetic route for the preparation of the new azetidinonecompounds mentioned in WO2011/017907 is too long, and double bonds of Zconfiguration cannot be produced stereoselectively, some of the stepsare not suitable for industrial production, therefore, it is necessaryto develop a new process route. The present invention provides a newmethod for preparing this kind of azetidinone. The raw materials of thenew process are easily obtained, and the process has a few syntheticsteps, the double bond of Z configuration can be producedstereoselectively, and the operation is simple, the yield is high, thecost is low, and the process can be used for industrial production.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to provide new keyintermediates (the compounds of formula III, IV and V) for thepreparation of the compound of formula (I) and the preparation methodsthereof:

From one aspect of the present invention, new intermediates of formulaIII, IV and V that can be used to prepare the compound of formula (I)are provided:

wherein, R¹ is C₁-C₆ alkyl, preferably methyl, ethyl or isopropyl, morepreferably methyl.

From another aspect of the present invention, a method for preparing thecompound of formula III is provided, said method comprising:

carrying out a Grignard addition selectively to the ketone of formula IIwith 4-fluorophenyl magnesium halide which is used as a Grignard reagentto obtain the tertiary alcohol of formula III:

wherein, R¹ is C₁-C₆ alkyl, preferably methyl, ethyl or isopropyl, morepreferably methyl; X is a halogen, preferably chlorine, bromine oriodine.

4-fluorophenyl magnesium halide is preferably 4-fluorophenyl magnesiumbromide.

The molar ratio of the compound of formula II to 4-fluorophenylmagnesium halide in the reaction is 1:1.0˜5.0, preferably 1:1.1˜3.0.

The temperature of the reaction is controlled between −78° C.˜−5° C.,preferably −50° C.˜−10° C.

From another aspect of the present invention, a method for preparing thecompound of formula IV is provided, the method comprising the followingstep: under the action of a dehydrating agent, the tertiary alcohol offormula III is dehydrated stereoselectively to obtain the(Z)-α,β-unsaturated ester of formula IV:

wherein, R¹ is C₁-C₆ alkyl, preferably methyl, ethyl or isopropyl, morepreferably methyl.

In the reaction, the dehydrating agent is selected from concentratedsulfuric acid, p-toluenesulfonic acid, phosphoric acid, triflicanhydride or methanesulfonic acid, preferably triflic anhydride.

In the reaction, the molar ratio of the compound of formula III to thedehydrating agent is 1:1.0˜3.0, preferably 1:1.0˜1.5.

The solvent of the reaction is selected from dichloromethane or toluene,preferably dichloromethane.

From another aspect of the invention, a method for preparing thecompound of formula V is provided, the method comprising: selectivelyreducing the ester of formula IV to the alcohol of formula V under theaction of a reducing agent:

wherein, R¹ is C₁-C₆ alkyl, preferably methyl, ethyl or isopropyl, morepreferably methyl.

The reducing agent of the reaction is preferably diisobutylaluminiumhydride (DIBAH).

The solvent of the reaction is selected from dichloromethane,tetrahydrofuran, toluene or dioxane, preferably toluene.

The molar ratio of the compound of formula IV to the reducing agent is1:2.5˜5.0, preferably 1:3.0˜4.0.

Another object of the present invention is to provide a new method forpreparing the compound of formula (I) according to the aboveintermediates, to further provide an improved and simple method forpreparing compound of formula (I) with good selectivity and high yield.

That is to say, a method for preparing the compound(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybut-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one, wherein the compound of formula (I) is a new azetidinonecompound that can reduce blood cholesterol.

The method comprising the following steps:

(1) Carrying out a Grignard addition selectively to the ketone offormula II with 4-fluorophenyl magnesium halide which is used as aGrignard reagent to obtain the tertiary alcohol of formula III:

wherein, R¹ is C₁-C₆ alkyl, preferably methyl, ethyl or isopropyl, morepreferably methyl; X is a halogen, preferably chlorine, bromine oriodine.

(2) Under the action of a dehydrating agent, the tertiary alcohol offormula III is dehydrated stereoselectively to obtain the(Z)-α,β-unsaturated ester of formula IV:

(3) Under the action of a reducing agent, the ester of formula IV isreduced selectively to the alcohol of formula V:

(4) Reacting the compound of formula V with a hydroxyl protectant toobtain the compound of formula VI:

wherein R² is an alcoholic hydroxyl protecting group, such as: acetyl,substituted or unsubstituted benzoyl (the “substituted” compriseshalogen, alkyl, nitro substituted) etc.

(5) Converting the carboxylic acid of formula VI into mixed anhydride oracyl halide, then reacting with (S)-4-phenyl-2-oxazolidone of formulaVII which is used as a chiral auxiliary to obtain a derivative ofoxazolidone of formula VIII:

wherein the carboxylic acid of formula VI is reacted with an acylatingagent to produce mixed anhydride; or the carboxylic acid of formula VIis reacted with phosphorus trihalide, phosphorus pentahalide,dichlorosulfane (SOCl₂), oxalyl chloride ((COCl)₂) or phosgene (COCl₂)to produce acyl halide; X is chlorine or bromine.

In addition, step (4) and step (5) can be combined i.e. the compound offormula VIII can be prepared from the compound of formula V through aone-pot method, the method comprises the following steps: protecting thealcoholic hydroxyl of formula V in a suitable solvent to obtain thecompound of formula VI, further converting the carboxylic acid offormula VI into mixed anhydride or acyl halide without separation andpurification, then reacting with (S)-4-phenyl-2-oxazolidone of formulaVII which is used as a chiral auxiliary to obtain a derivative ofoxazolidone of formula VIII:

wherein the carboxylic acid of formula VI is reacted with an acylatingagent to produce mixed anhydride; or the carboxylic acid of formula VIis reacted with phosphorus trihalide, phosphorus pentahalide,dichlorosulfane (SOCl₂), oxalyl chloride ((COCl)₂) or phosgene (COCl₂)to produce acyl halide; X is chlorine or bromine.

(6) Under the presence of Lewis acids (titanium tetrachloride (TiCl₄)and tetraisopropyl titanate) and tertiary amine, reacting the derivativeof oxazolidone of formula VIII with the imine of formula IX to obtain anaddition product of formula XI:

wherein R² and R³ are all hydroxyl protecting groups, such as: acetyl,substituted or unsubstituted benzoyl (the “substituted” compriseshalogen, alkyl, nitro substituted) etc., R² and R³ can be the same ordifferent.

(7) Carrying out a cyclization for the addition product of formula XI byusing N,O-bis(trimethylsilyl)acetamide (BSA) and tetrabutylammoniumfluoride (TBAF) to obtain the β-lactams of formula XII, XIII and XIV:

(8) Obtaining the compound of formula (I) via the deprotection of themixture of the compounds of formula XII, XIII and XIV in step (7) underthe action of alkali:

In the above reaction steps, wherein, R¹ is C₁-C₆ alkyl, preferablymethyl, ethyl or isopropyl, more preferably methyl; R² and R³ are allhydroxyl protecting groups, such as: acetyl, substituted orunsubstituted benzoyl (the “substituted” comprises halogen, alkyl, nitrosubstituted) etc., R² and R³ can be the same or different.

In step (1), the molar ratio of the compound of formula II to4-fluorophenyl magnesium halide is 1:1.0˜5.0, preferably 1:1.1˜3.0;4-fluorophenyl magnesium halide is preferably 4-fluorophenyl magnesiumbromide. The reaction temperature is controlled between −78° C.˜−5° C.,preferably −50° C.˜−10° C.

In step (2), the dehydrating agent is selected from concentratedsulfuric acid, p-toluenesulfonic acid, phosphoric acid, triflicanhydride or methanesulfonic acid, preferably triflic anhydride. Themolar ratio of the compound of formula III to the dehydrating agent is1:1.0˜3.0, preferably 1:1.0˜1.5. The solvent of the reaction is selectedfrom dichloromethane or toluene, preferably dichloromethane.

In step (3), the molar ratio of the compound of formula IV to thereducing agent is 1:2.5˜5.0, preferably 1:3.0˜4.0. The reducing agent ispreferably diisobutylaluminium hydride (DIBAH). The solvent of thereaction is selected from dichloromethane, tetrahydrofuran, toluene ordioxane, preferably toluene.

In step (4), the alcoholic hydroxyl protecting group R² is preferablysubstituted or unsubstituted benzoyl, more preferably substitutedbenzoyl, wherein the “substituted” is preferably substituted by nitro,more preferably substituted by nitro at the 3-position. The solvent ofthe reaction is selected from N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO),1,3-dimethylpropyleneurea (DMPU) or hexamethylphosphoramide (HMPA),preferably N,N-dimethylacetamide (DMA). The molar ratio of the compoundV to the hydroxyl protecting agent is 1:1.0˜3.0, preferably 1:1.2˜2.3.

In step (5), the acylating agent is selected from pivaloyl chloride,3-nitrobenzoyl chloride or isobutyl chloroformate, preferably pivaloylchloride or 3-nitrobenzoyl chloride. The molar ratio of the compound offormula VI to the acylating agent is 1:1.0˜2.0, preferably 1:1.1˜1.6.The molar ratio of the compound of formula VI to(S)-4-phenyl-2-oxazolidone of formula VII is 1:0.5˜1.5, preferably1:0.8˜1.1.

When the step (4) is combined with the step (5), i.e., the compound offormula VIII is prepared from the compound of formula V through aone-pot method, the alcoholic hydroxyl protecting group R² is preferablysubstituted or unsubstituted benzoyl, more preferably substitutedbenzoyl, wherein the “substituted” is preferably substituted by nitro,more preferably substituted by nitro at the 3-position. The solvent isselected from N,N-dimethyl formamide (DMF), N,N-dimethylacetamide (DMA),dimethylsulfoxide (DMSO), 1,3-dimethylpropyleneurea (DMPU) orhexamethylphosphoramide (HMPA), preferably N,N-dimethylacetamide (DMA).The molar ratio of the compound V to the alcoholic hydroxyl protectingagent is 1:1.0˜3.0, preferably 1:1.0˜1.5. The acylating agent isselected from pivaloyl chloride, 3-nitrobenzoyl chloride or isobutylchloroformate, preferably pivaloyl chloride or 3-nitrobenzoyl chloride.The molar ratio of the compound of formula V to the acylating agent is1:1.0˜2.0, preferably 1:1.0˜1.5. The molar ratio of the compound offormula V to (S)-4-phenyl-2-oxazolidone is 1:0.5˜1.5, preferably1:0.7˜1.1.

In step (6), the phenolic hydroxyl protecting group R³ is preferablysubstituted or unsubstituted benzoyl, more preferably substitutedbenzoyl, wherein the “substituted” is preferably substituted by nitro,more preferably substituted by nitro at the 3-position. The tertiaryamine is preferably diisopropylethylamine (DIPEA). The molar ratio ofthe compound of formula VIII to the imine (the compound of formula IX)is 1:1.0˜2.0, preferably 1:1.0˜1.2; wherein the reaction temperature iscontrolled between −90° C.˜0° C., preferably −80° C.˜−20° C.; whereinalcohols, acids or mixed liquids of acids diluted by organic solventscan be used in the post-processing quenching reaction; wherein thealcohols are selected from methanol, ethanol, propanol, isopropanol,tertiary butanol, preferably isopropanol; wherein the acids are selectedfrom inorganic acids and organic acids, comprising hydrochloric acid,sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid,trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonicacid, benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, citricacid, maleic acid or tartaric acid, preferably organic acids, comprisingformic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, benzoic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, maleic acid or tartaric acid, morepreferably acetic acid or trifluoroacetic acid.

In step (7), the solvent of the reaction is selected from acetonitrileor toluene, preferably toluene. The molar ratio of the compound offormula XI to N,O-bis(trimethylsilyl)acetamide (BSA) is 1:1.0˜5.0,preferably 1:2.0˜4.0; and the molar ratio of the compound of formula XIto tetrabutylammonium fluoride trihydrate (TBAF) is 1:0.1˜0.5,preferably 1:0.1˜0.3.

In step (8), the solvent used for the deprotection of the compounds offormula XII, XIII and XIV is preferably acetone, the alkali ispreferably aqueous lithium hydroxide. The molar ratio of the alkali tothe compound XI in step (7) is 3.0˜5.0:1.

In another aspect, the present invention also relates to the protectionof the intermediates of formula III, IV and V.

Some of the terms used in the present invention are defined as follows:

The “halogen” refers to fluorine, chlorine, bromine and iodine.

The “alkyl”, when it is a group or a part of a group, it refers to alinear or branched aliphatic hydrocarbon group. Most preferably, it is aC₁˜C₆ alkyl, unless otherwise stated, the examples of a linear orbranched C₁˜C₆ alkyl comprising, but is not limited to: methyl, ethyl,n-propyl, 2-propyl, n-butyl, isobutyl, tertiary butyl, hexyl and so on.

The “room temperature” refers to 20˜30° C.

The preferred reaction conditions of the present invention are listed inthe following schemes:

Step (1):

Step (2):

Step (3):

Step (4):

Step (5):

Step (6):

Step (7):

Step (8):

In the above reaction schemes, Tf₂O is triflic anhydride, DIBAH isdiisobutylaluminium hydride, DMAP is 4-dimethylamino-pyridine, DIPEA isdiisopropylethylamine, BSA is N,O-bis(trimethylsilyl)acetamide, and TBAFis tetrabutylammonium fluoride, wherein R¹ is C₁-C₆ alkyl, preferablymethyl, ethyl or isopropyl, more preferably methyl; R² and R³ are allhydroxyl protecting groups, such as: acetyl, substituted orunsubstituted benzoyl (the “substituted” comprises halogen, alkyl, nitrosubstituted) etc., R² and R³ can be the same or different.

DETAILED DESCRIPTION OF THE PRESENT APPLICATION

The preparation method will be further illustrated with the combinationof the above reaction steps (1)˜(8) below.

In step (1), the alcohol of formula III is produced via the addition ofthe keto-carbonyl of formula II and a Grignard reagent. The reactionprocess is as follows: the compound of formula II (1 equivalent) isadded into an anhydrous solvent (such as tetrahydrofuran or diethylether, preferably tetrahydrofuran), the temperature is decreased tobetween −78° C.˜−5° C. (preferably −50° C.˜−10° C.), 1.0˜5.0 equivalents(preferably 1.1˜3.0 equivalents) Grignard reagent (such as4-fluorophenyl magnesium halide, preferably 4-fluorophenyl magnesiumbromide) is added, then the temperature is kept for the reaction for 1˜2hours under stirring, the reaction is terminated by aqueous ammoniumchloride. The product, the compound of formula III is separated viaextraction and is purified via crystallization.

In the reaction, the raw material, carboxylic ketoester (the compound offormula II) can be obtained via the synthesis method in the document,Tetrahedron Letters, 1994, 35, 6089-6092, i.e. in the acetonitrilesolvent, the ketone of formula II is obtained via the oxidation andring-opening of cyclopentanone-2-carboxylate under the catalyzation ofcupric salt (such as CuCl₂.2H₂O, CuSO₄.5H₂O, Cu(OAc)₂.H₂O or Cu(ClO₄)₂.6H₂O). The equation is as follows:

In step (2), the (Z)-α,β-unsaturated ester of formula IV is produced viathe stereoselective dehydration of the tertiary alcohol of formula Ill.It is reported in J. Org. Chem. 2006, 71, 5039-5042 that(Z)-α-aryl-α,β-unsaturated ester is obtained via selective dehydrationof α-aryl-α-hydroxyl ester under the action of dehydrating agent(triflic anhydride) and alkali (such as pyridine or DMAP). The reactiontime reported in the literature is long (the reaction lasts 10˜12 hoursat room temperature), and it is not reported whetherw-carbonyl-α-aryl-α-hydroxyl ester is suitable for the reaction. Thereaction of the prior art is improved by the method of the presentinvention to increase the efficiency and selectivity of producing(Z)-ω-carbonyl-α-aryl-α,β-unsaturated ester. After the improvement, thereaction time is shortened, the selectivity is improved and alkali(pyridine or DMAP) catalyzation is no longer needed. Carboxylic acidhydroxyl ester (the compound of formula III, 1 equivalent) is dissolvedin a non-polar anhydrous solvent (such as dichloromethane), 1.0˜3.0equivalents (preferably 1.0˜1.5 equivalents) dehydrating agent(preferably triflic anhydride) is added at 5° C.˜15° C., the reactionwas refluxed for 1˜2 hours and then is terminated by water. The product,the compound of formula IV is separated via extraction.

In step (3), the ester group of the compound of formula IV is reducedselectively and the carbonyl group is retained. The compound of formulaIV (1 equivalent) is dissolved in a suitable solvent (preferablytoluene), alkali (such as triethylamine or diisopropylethylamine) isadded at room temperature to allow the carbonyl group to form a salt,then the temperature is decreased, 2.5˜5.0 equivalents (preferably3.0˜4.0 equivalents) reducing agent (preferably diisobutylaluminiumhydride) is added slowly at the temperature of −30° C.˜−5° C., thereaction is stirred for 20˜60 minutes. After completion of the reaction,the reaction solution is added slowly to alkali (such as aqueouspotassium hydroxide, lithium hydroxide or sodium hydroxide, preferablyaqueous sodium hydroxide) at the temperature of t<15° C., stirred,layered, the water phase is extracted by a suitable solvent (such asdichloromethane) to remove organic impurities, then is acidified by anacid (such as hydrochloric acid), then it is extracted by a suitablesolvent (such as ethyl acetate), the product is separated and purifiedvia crystallization to obtain(Z)-5-(4-fluorophenyl)-6-hydroxyl-hex-4-enoic acid (the compound offormula V).

In step (4), the hydroxyl group of the compound of formula V isprotected selectively and the carbonyl group is retained. The compoundof formula V (1 equivalent) is dissolved in a suitable anhydrous solvent(preferably N,N-dimethylacetamide), 1.0˜3.0 equivalents (preferably1.2˜2.3 equivalents) hydroxyl protecting agent (preferably nitrobenzoylchloride, more preferably 3-nitrobenzoyl chloride) is added at −5°C.˜40° C. and reacted for 5˜6 hours. Suitable alkali (such as pyridine)is added to hydrolyze the resulting mixed anhydride, then alkali (suchas imidazole) is added to remove the carboxylic acid of the protectingagent liberated from hydrolysis by forming a salt. The product, thecompound of formula VI is separated via extraction.

In step (5), the compound of formula VI (1 equivalent) is dissolved inan anhydrous inert solvent (such as tetrahydrofuran or dichloromethane,preferably dichloromethane), 1.0˜2.0 equivalents (preferably 1.1˜1.6equivalents) acylating agent (such as pivaloyl chloride, isobutylchloroformate or 3-nitrobenzoyl chloride, preferably pivaloyl chlorideor 3-nitrobenzoyl chloride) is added, at the same time, the mixture isreacted for 3˜4 hours at room temperature in the presence of alkali(such as triethylamine) to obtain the mixed anhydride. Then 0.5˜1.5equivalents (preferably 0.8˜1.1 equivalents) (S)-4-phenyl-2-oxazolidoneof formula VII is added to the obtained mixed anhydride solution,0.1˜0.3 equivalent suitable catalyst (such as 4-dimethylaminopyridine)is added and stirred for 3˜5 hours at room temperature to form anacylated derivative of oxazolidone of formula VIII via condensation. Theproduct is separated via extraction and is purified via crystallization.

In addition, step (4) can be combined with step (5), the compound offormula VIII can be produced from the compound of formula V through anone-pot method. The compound of formula V (1 equivalent) is dissolved ina suitable anhydrous solvent (preferably N,N-dimethylacetamide), 1.0˜3.0equivalents (preferably 1.0˜1.5 equivalents) hydroxyl protecting agent(preferably nitrobenzoyl chloride, preferably 3-nitrobenzoyl chloride)is added at −5° C.˜40° C., after the completion of the reaction, thereaction solution is added to the solution of 1.0˜2.0 equivalents(preferably 1.0˜1.5 equivalents) acylating agent (such as pivaloylchloride, isobutyl chloroformate or 3-nitrobenzoyl chloride, preferablypivaloyl chloride or 3-nitrobenzoyl chloride, more preferably3-nitrobenzoyl chloride) and alkali (such as triethylamine) dissolved inthe anhydrous inert solvent (such as tetrahydrofuran or dichloromethane,preferably dichloromethane), then 0.5˜1.5 equivalents (preferably0.7˜1.1 equivalents) chiral auxiliary ((S)-4-phenyl-2-oxazolidone) offormula VII and 0.1˜0.5 equivalent suitable catalyst (such as4-dimethylamino-pyridine) are added, the temperature was kept for thereaction for 6˜7 hours, the acylated derivative of oxazolidone offormula VIII is produced via condensation. The product is separated viaextraction and is purified via crystallization.

In step (6), the temperature is decreased at the presence of a suitableanhydrous solvent (such as anhydrous dichloromethane) and the protectionof a dry inert gas flow (such as nitrogen), Lewis acids TiCl₄ (1.1˜1.5equivalents) and tetraisopropyl titanate (0.3˜0.5 equivalent) are addedat the temperature of −5° C.˜0° C. to react under stirring for 20˜40minutes to produce titanium reagent, which is retained to be used. Theacylated derivative of oxazolidone of formula VIII (1 equivalent), theprotected imine compound of formula IX (1.0˜2.0 equivalents, preferably1.0˜1.2 equivalents) are dissolved in anhydrous solvent (such asanhydrous dichloromethane), tertiary amine (such asdiisopropylethylamine) is added, stirred for 10 minutes, the temperatureis decreased, the titanium reagent produced above is added slowly dropby drop at the temperature of −90° C.˜0° C. (preferably −80° C.˜−20°C.), the temperature was kept for the reaction continuously, after thecompletion of the reaction, a suitable amount of acid (preferably aceticacid or trifluoroacetic acid) is added to quench the reaction.Meanwhile, the titanium salt is removed by adding dilute sulphuric acid,then the compound of formula XI is separated via extraction and purifiedvia crystallization.

In step (7), the compound of formula XI (1 equivalent) is dissolved in asuitable solvent (such as toluene), 1.0˜5.0 equivalents (preferably2.0˜4.0 equivalents) N,O-bis(trimethylsilyl)acetamide (BSA) is added,and reacted for 2˜3 hours at the temperature of 50° C.˜70° C., then0.1˜0.5 equivalent (preferably 0.1˜0.3 equivalent) tetrabutylammoniumfluoride (TBAF) is added, reacted for 2˜5 hours at the temperature, themixture of the compounds of formula XII, XIII and XIV are produced viacyclization.

In step (8), the mixture of the compounds of formula XII, XIII and XIVis dissolved in a suitable solvent (preferably acetone), 3˜5 equivalents(it is calculated based on that the feed amount of the compound XI instep 7 as 1 equivalent) alikali (preferably aqueous lithium hydroxide)is added at room temperature to hydrolyze the hydroxyl protecting group,the mixture is reacted under stirring for 2˜3 hours, then acidified witha weak acid (such as diluted sulphuric acid or diluted hydrochloricacid), extracted, concentrated and separated via column chromatographyto obtain the compound of formula I, which is purified viarecrystallization.

In the present invention, the carboxylic ketoester represented byformula (II) is used as the raw material and is subjected to Grignardaddition, stereoselective dehydration, ester group reduction, hydroxylgroup protection, addition with imine after condensation with a chiralauxiliary, cyclization and deprotection to obtain the compoundrepresented by formula (I). The advantages of the present invention canbe summarized as follows:

a) Compared with the preparation method reported in WO 2011/017907, thenumber of synthetic steps are significantly decreased, from 14 steps to8 steps; at the same time, the column chromatography is replaced bymultiple times of recrystallization to simplify the purificationoperation and decrease the cost.b) In step 2 of the present method, the Z alkene is obtained viastereoselection, allowing the subsequent multistep reactions to startwith a single isomer, which simplify the separation operation anddecrease the cost.c) In order to protect the hydroxyl groups (including alcoholic hydroxylgroups and phenolic hydroxyl groups), nitro substituted benzoyl is used,preferably the benzoyl with nitro substituted at 3-position is used.From one aspect, the ability of crystallization of the key intermediateis enhanced so that it can be purified effectively in a simplecrystallization operation; from another aspect, it is advantageous forthe deprotection under mild environment subsequently and prevent theoccurrence of the accompanied side reactions (such as the open of theβ-lactam ring) under alkaline condition.d) The method of the present invention is suitable for industrializedproduction and the yield is high.

In summary, the present invention has advantages of easily available rawmaterials, a few synthetic steps, simple operation, high yield, goodstereoselectivity and low cost, and can be used for industrialproduction.

EMBODIMENTS

The following examples are solely for the illustration of the presentinvention, the present invention is not limited by those examples.

Example 1: Preparation of Raw Material Imine IXa

Step 1: 12 Kg 4-hydroxybenzaldehyde and 60 L methanol were added to a100 L reaction tank and were dissolved under stirring, 12 Kg4-fluoroaniline was added drop by drop at room temperature, the mixturewas reacted continuously for 2˜3 hours after the addition. The reactionwas monitored by TLC until the spots of the raw material(4-hydroxylbenzaldehyde) disappeared, the solid produced by the reactionwas filtered, dried and weighted 19 Kg (yield: 90%).

¹H NMR (400 MHz, DMSO-d₆): δ 6.88 (d, 2H, J=8.4 Hz), 7.18-7.27 (m, 4H),7.76 (d, 2H, J=8.4 Hz), 8.46 (s, 1H), 10.11 (s, 1H).

Step 2: The product obtained in step 1 and 200 L dichloromethane wereadded to a 500 L reaction tank and were dissolved under stirring, 22 Kgtriethylamine, 1.8 Kg 4-dimethylamino-pyridine (DMAP) were added at roomtemperature, 50 L dichloromethane solution with 20 Kg 3-nitrobenzoylchloride dissolved were added drop by drop, the mixture was reactedcontinuously for 2˜3 hours after the addition and monitored by TLC untilthe spots of the raw material (the product obtained from step 1)disappeared. The pH was adjusted to 4˜6 by 2M hydrochloric acid, thesolution was settled into layers, the organic phase was collected, thewater phase was extracted by dichloromethane (30 L×2 times), the organicphases were combined and then washed 1 time with brine, dried overanhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure, the crude product was recrystallized in anhydrousethanol, filtered and dried to obtain 19 Kg imine IXa (yield: 59%).

¹H NMR (400 MHz, DMSO-d₆): δ 7.23 (t, 2H, J=8.8 Hz), 7.31-7.35 (m, 2H),7.49 (d, 2H, J=8.4 Hz), 7.90 (t, 1H, J=8.0 Hz), 8.03 (d, 2H, J=8.4 Hz),8.52-8.58 (m, 2H), 8.65 (s, 1H), 8.78 (s, 1H).

Example 2: Preparation of5-(4-fluorophenyl)-5-hydroxy-6-methoxy-6-oxo-hexanoic acid (IIIa)

100 g (0.563 mol) 6-methoxy-5,6-dioxo-hexanoic acid (compound IIa) and300 mL tetrahydrofuran were added to a 3 L reaction flask, the mixturewas protected under nitrogen and was dissolved under stirring, thetemperature was decreased to −20° C.˜−10° C., 1M solution of4-fluorophenyl magnesium bromide in THF (1.4 L, 1.4 mol) was addedslowly drop by drop, the temperature was kept for the reaction for 1˜2hours after the addition. The reaction was monitored by TLC until thespots of the raw material (compound IIa) disappeared.

A solution of 25% aqueous ammonium chloride (60 g ammonium chloridedissolved in 180 mL water) was added at the temperature of −20° C.˜0° C.and was stirred for 5 minutes, then the pH was adjusted to 3˜5 by 4Mhydrochloric acid at the temperature of 0° C.˜30° C., then 600 mLn-heptane was added and stirred for 5 minutes, the solution was settledinto layers, the organic phase was collected, the water phase wasextracted with ethyl acetate (140 mL×2 times), the organic phases werecombined and then washed 2 times with saturated salt water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure, the crude product was recrystallized in toluene,filtered and dried to obtain 64.6 g compound IIIa (HPLC purity: 93.2%;yield: 39.6%).

¹H NMR (DMSO-d₆): 1.33-1.43 (m, 2H), 1.89-1.96 (m, 1H), 1.99-2.04 (m,1H), 2.15 (t, 2H, J=7.6 Hz), 3.61 (s, 3H), 5.99 (s, 1H), 7.12-7.17 (m,2H), 7.47-7.51 (m, 2H), 12.02 (s, 1H); MS (m/z): 269 [M−H]⁻.

Example 3: Preparation of(Z)-5-(4-fluorophenyl)-6-methoxy-6-oxo-hex-4-enoic acid (IVa)

64.0 g (0.221 mol) 5-(4-fluorophenyl)-5-hydroxy-6-methoxy-6-oxo-hexanoicacid (compound IIIa) and 300 mL dichloromethane were added to a 500 mLreaction flask, the mixture was dissolved under stirring and wasprotected under nitrogen, the temperature was decreased, 65.6 g (0.233mol) triflic anhydride was added at the temperature of 5° C.˜15° C.,then the reaction mixture was refluxed for 1˜2 hours and monitored byTLC until the spots of the raw material (compound IIIa) disappeared.

The temperature was decreased, 100 mL water was added at the temperatureof 5° C. 15° C. to quench the reaction, the solution was settled intolayers, the organic phase was collected, the water phase was extractedwith dichloromethane (60 mL×2 times), the organic phases were combinedand then washed 3 times with saturated salt water, dried over anhydroussodium sulfate, filtered and evaporated to dryness under reducedpressure to obtain 54.4 g compound IVa (HPLC purity: 95.6%; yield:93.4%).

¹H NMR (DMSO-d₆): 2.42 (t, 2H, J=7.3 Hz), 2.56 (q, 2H, J=7.3 Hz), 3.74(s, 3H), 6.27 (t, 1H, J=7.4 Hz), 7.18 (t, 2H, J=8.8 Hz), 7.32-7.36 (m,2H), 12.19 (s, 1H).

Example 4: Preparation of (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoicacid (V)

54.0 g (0.205 mol) (Z)-5-(4-fluorophenyl)-6-methoxy-6-oxo-hex-4-enoicacid (compound IVa) and 240 mL toluene were added to a 1 L reactionflask, the mixture was dissolved under stirring and was protected undernitrogen, 31.0 g (0.240 mol) diisopropylethylamine was added and wasdissolved under stirring, the temperature was decreased to −20° C.˜−15°C., 382.0 g (0.673 mol) DIBAH toluene solution (25%) was added slowlydrop by drop, the temperature was kept for the reaction for 20˜40minutes after the addition. The reaction was monitored by TLC until theraw material (compound IVa) reacted completely.

Below the temperature of 15° C., the reaction mixture was added slowlyto aqueous sodium hydroxide (72.2 g sodium hydroxide dissolved in 300 mLwater) drop by drop, then the solution was stirred for 30 minutes;settled into layers, the water phase was collected, the water phase wasextracted with dichloromethane (60 mL×2 times), the dichloromethanephase was discarded. The pH of the water phase was adjusted to 1˜2 with4M hydrochloric acid below the temperature of 2500, 240 mL ethyl acetatewas added, the solution was stirred for 5 minutes then was settled intolayers, the organic phase was collected, and the water phase wasextracted with ethyl acetate (100 mL×3 times). The organic phases werecombined and washed 2 times with saturated salt water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure, the crude product was recrystallized in toluene,filtered and dried to obtain 36.4 g compound V (HPLC purity: 96.3%;yield: 76.4%).

¹H NMR (DMSO-d₆): 2.38 (t, 2H, J=7.1 Hz), 2.47 (q, 2H, J=7.0 Hz), 4.34(s, 2H), 4.75 (br s, 1H), 5.78 (t, 1H, J=7.2 Hz), 7.13 (t, 2H, J=8.9Hz), 7.45-7.48 (m, 2H), 12.13 (br s, 1H).

Example 5: Preparation of(Z)-5-(4-fluorophenyl)-6-(3-nitrobenzoyloxy)hex-4-enoic acid (VIa)

18.0 g (0.077 mol) (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid(compound V) and 60 mL N,N-dimethylacetamide were added to a 250 mLreaction flask, the mixture was dissolved under stirring and wasprotected under nitrogen, the temperature was decreased, 31.2 g (0.168mol) 3-nitrobenzoyl chloride was added at the temperature of −5° C.˜5°C., then the reaction mixture was reacted for 5˜6 hours at thetemperature of −5° C.˜5° C. and monitored by TLC until the spots of theraw material (compound V) disappeared.

At the temperature of 0˜10° C., aqueous pyridine (13.0 g pyridinedissolved in 30 mL water) was added and stirred for 30 minutes, then atthe temperature of 0˜10° C., aqueous imidazole (22.5 g imidazoledissolved in 50 mL water) was added, stirred for 1˜2 hours, then thesolution was extracted with 120 mL ethyl acetate and settled intolayers, the organic phase was collected, and the water phase wasextracted with ethyl acetate (20 mL×3 times), the organic phases werecombined, and the organic phase was washed with water, the pH wasadjusted to 3˜5 with 2M hydrochloric acid, then the organic phase waswashed 1 time with saturated salt water, dried over anhydrous sodiumsulfate, filtered and evaporated to dryness under reduced pressure toobtain 24.0 g compound VIa (HPLC purity: 92.6%; yield: 77.0%).

¹H NMR (DMSO-d₆): 2.45 (t, 2H, J=7.1 Hz), 2.59 (q, 2H, J=7.3 Hz), 5.36(s, 2H), 6.09 (t, 1H, J=7.4 Hz), 7.18 (t, 2H, J=8.8 Hz), 7.51-7.54 (m,2H), 7.80 (t, 1H, J=7.8 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.46-8.48 (m, 2H),12.17 (s, 1H).

Example 6: Preparation of[(Z)-2-(4-fluorophenyl)-6-oxo-6-[(4S)-2-oxo-4-phenyl-oxazolidin-3-yl]hex-2-enyl]3-nitrobenzoate(VIIIa)

24.0 g (0.060 mol)(Z)-5-(4-fluorophenyl)-6-(3-nitrobenzoyloxy)-hex-4-enoic acid (compoundVIa) and 100 mL dichloromethane were added to a 250 mL reaction flask,the mixture was dissolved under stirring and was protected undernitrogen. 8.9 g (0.074 mol) pivaloyl chloride was added. At roomtemperature, 15.6 g (0.154 mol) triethylamine was added slowly drop bydrop, the reaction mixture was reacted for 3˜4 hours at room temperatureafter the addition. Then 7.8 g (0.048 mol) (S)-4-phenyl-2-oxazolidinone(compound VII) and 2.2 g (0.018 mol) 4-dimethylaminopyridine were addedand reacted at room temperature for 3˜4 hours. The reaction wasmonitored by TLC until the spots of the raw material (compound VIa)disappeared.

The pH was adjusted to 4˜6 with 2M hydrochloric acid, the solution wassettled into layers, the organic phase was collected and the water phasewas extracted with dichloromethane (30 mL×2 times), the organic phaseswere combined. Aqueous imidazole (11.1 g imidazole dissolve in 30 mLwater) was added and stirred for 1˜2 hours, then was washed 1 time withsaturated salt water, dried over anhydrous sodium sulfate, filtered andevaporated to dryness under reduced pressure. The crude product wasrecrystallized in toluene, filtered and dried to obtain 25.3 g compoundVIIIa (HPLC purity: 95.1%; yield: 78.0%).

¹H NMR (DMSO-d₆): 2.59 (q, 2H, J=7.2 Hz), 3.00-3.18 (m, 2H), 4.15 (dd,1H, J=8.8, 3.6 Hz), 4.72 (t, 1H, J=8.7 Hz), 5.29 (d, 1H, J=13.2 Hz),5.32 (d, 1H, J=13.2 Hz), 5.45 (dd, 1H, J=8.6, 3.6 Hz), 6.05 (t, 1H,J=7.5 Hz), 7.17 (t, 2H, J=8.9 Hz), 7.26-7.36 (m, 5H), 7.46-7.50 (m, 2H),7.76-7.80 (m, 1H), 8.19-8.21 (m, 1H), 8.45-8.47 (m, 2H).

Example 7: Preparation of the Compound of Formula VIIIa

Step 1: 18 g (0.080 mol) (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoicacid (compound V) and 90 mL N,N-dimethylacetamide were added to a 250 mLreaction flask, the mixture was dissolved under stirring and wasprotected under nitrogen. 17.8 g (0.096 mol) 3-nitrobenzoyl chloride wasadded at 25° C.˜30° C., the temperature was kept for the reaction for 2hours, the reaction was determined to be complete by HPLC, the reactionmixture was retained to be used.

Step 2: 180 mL dichloromethane and 16.3 g (0.088 mol) 3-nitrobenzoylchloride were added to a 500 mL reaction flask and were protected undernitrogen, 32.4 g (0.32 mol) triethylamine was added drop by drop at thetemperature of 25° C.˜30° C., then the reaction mixture of step 1 wasadded drop by drop at the temperature of 25° C.˜30° C. (the mixture wasadded within 1˜2 hours), then the temperature was kept for the reactionfor 5 minutes after the addition, then 11.75 g (0.072 mol)(S)-4-phenyl-2-oxazolidinone and 4.4 g (0.036 mol)4-dimethylamino-pyridine were added, the temperature was kept for thereaction for 6˜7 hours, the reaction was determined to be complete byHPLC.

90 mL water was added to the reaction mixture, the solution was settledinto layers, the organic phase was collected and the water phase wasextracted with dichloromethane (50 mL×2 times), the organic phases werecombined. The pH of the organic phase was adjusted to 4˜6 with 2Mhydrochloric acid, then the organic phase was washed with 90 mL wateruntil it is neutral, then aqueous imidazole (27 g imidazole dissolved in50 mL water) was added, stirred for 30 minutes and settled into layers,the organic phase was collected and was washed with saturated saltwater, dried over anhydrous sodium sulfate, filtered and evaporated todryness under reduced pressure. The crude product was recrystallized inthe mixed solvent of ethyl acetate/petroleum ether (2/3), filtered anddried to obtain 30 g compound VIIIa (HPLC purity: 97.5%; yield: 74.0%).

Example 8: Preparation of[(Z,5R)-5-[(S)-(4-fluoroanilino)-[4-(3-nitrobenzoyl)oxyphenyl]methyl]-2-(4-fluorophenyl)-6-oxo-6-[(4S)-2-oxo-4-phenyl-oxazolidin-3-yl]hex-2-enyl]3-nitrobenzoate(XIa)

80 mL dichloromethane and 10.5 g (0.055 mol) titanium tetrachloride wereadded to a 250 mL reaction flask and were protected under nitrogen, thetemperature was decreased, 5.2 g (0.018 mol) titanium isopropylate wasadded drop by drop at the temperature of −5° C.˜0° C., then the solutionwas stirred for 30 minutes at the temperature of −5° C.˜0° C. to obtaintitanium reagent. 25.0 g (0.046 mol) compound of formula VIIIa, 18.3 g(0.050 mol) imine of formula IXa and 350 mL dichloromethane were addedto a 1 L reaction flask and were dissolved under stirring, 14.3 g (0.111mol) diisopropylethylamine was added and stirred, the temperature wasdecreased, the titanium reagent was added slowly drop by drop at thetemperature of −25° C.˜−20° C., then the mixture was reacted for 1˜2hours at the temperature of −25° C.˜−20° C., the reaction was monitoredby HPLC until the content of the raw material (compound VIIIa) was <5%.

30 mL acetic acid was added drop by drop at the temperature of −25°C.˜−20° C. and stirred for 5 minutes; 150 mL sulfuric acid (2M) wasadded drop by drop below 10° C. and stirred for 10 minutes; the solutionwas settled into layers, the organic phase was collected, the waterphase was extracted with dichloromethane (25 mL×2 times), the organicphases were combined and washed 3 times with saturated salt water, driedover anhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure. The crude product was recrystallized in toluene,filtered and dried to obtain 21.4 g compound XIa (HPLC purity: 95.3%;yield: 50.4%).

¹H NMR (DMSO-d₆): 2.38-2.45 (m, 1H), 2.56-2.64 (m, 1H), 4.11 (dd, 1H,J=8.8, 4.7 Hz), 4.62-4.75 (m, 3H), 5.15 (s, 2H), 5.51 (dd, 1H, J=8.5,4.6 Hz), 5.98 (t, 1H, J=7.4 Hz), 6.34 (d, 1H, J=9.8 Hz), 6.58-6.62 (m,2H), 6.80 (t, 2H, J=8.9 Hz), 7.13-7.28 (m, 9H), 7.45-7.48 (m, 2H), 7.54(d, 2H, J=8.5 Hz), 7.79 (t, 1H, J=7.9 Hz), 7.91 (t, 1H, J=8.0 Hz), 8.18(d, 1H, J=7.8 Hz), 8.43-8.49 (m, 3H), 8.57-8.60 (m, 1H), 8.74 (t, 1H,J=1.8 Hz); MS (m/z): 883 [M+H]⁺.

Example 9: Preparation of the Compound of Formula XIa

150 mL dichloromethane and 13.2 g (0.069 mol) titanium tetrachloridewere added to a 500 mL reaction flask, were protected under nitrogen andwere stirred, the temperature was decreased, 60 mL dichloromethanesolution with 6.6 g (0.023 mol) titanium isopropylate dissolved wasadded drop by drop at the temperature of −5° C.˜0° C., then the solutionwas stirred for 30 minutes at the temperature of −5° C.˜0° C. to obtaintitanium reagent. 30 g (0.058 mol) compound of formula VIIIa, 23.2 g(0.064 mol) imine of formula IXa and 900 mL dichloromethane were addedto a 2 L reaction flask and were protected under nitrogen and weredissolved under stirring, 19.5 g diisopropylethylamine was added, thetemperature was decreased, the titanium reagent prepared above was addedslowly drop by drop at the temperature of −75° C.˜−70° C., the additionwas terminated within about 2 hours, then the reaction mixture wasreacted for 5 minutes at the temperature of −75° C.˜−70° C. andmonitored by HPLC until the spots of the raw material (compound VIIIa)disappeared.

A solution of 135 mL 20% trifluoroacetic acid in dichlormethane wasadded quickly below the temperature of −70° C. and was stirred for 1minute; 240 mL aqueous sulfuric acid (2M) was added quickly drop by dropbelow −30° C., then the solution was stirred and was warmed to roomtemperature; the solution was settled into layers, the organic phase wascollected, the water phase was extracted with dichloromethane (100 mL×2times), the organic phases were combined and washed with saturated saltwater until it is neutral, dried over anhydrous sodium sulfate, filteredand evaporated to dryness under reduced pressure to obtain crudeproduct. The crude product was recrystallized in the mixed solvent ofethyl acetate/petroleum ether (1/1), filtered and dried to obtain 35 gcompound XIa (HPLC purity: 98.9%; yield: 68.7%).

Example 10: Preparation of(3R,4S)-4-[4-(3-nitrobenzoyloxy)phenyl]-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(XIIa),(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(XIIIa),(3R,4S)-4-(4-trimethylsilyloxyphenyl)-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(XIVa)

21.0 g (0.025 mol) compound of formula XIa and 200 mL toluene were addedto a 500 mL reaction flask, the mixture was stirred and heated, 18.4 g(0.090 mol) N,O-bis(trimethylsilyl)acetamide (BSA) was added at thetemperature of 50° C.˜60° C., then reacted for 2 hours at thistemperature; then 1.0 g (0.003 mol) tetrabutylammonium fluoridetrihydrate was added at the temperature of 50° C.˜60° C. and reacted for2˜3 hours at that temperature. The reaction was monitored by HPLC untilthe content of the raw material (compound XIa) was <1.0%.

The temperature was decreased below 25° C., 50 mL ice water was addeddrop by drop and stirred for 10 minutes, then 180 mL n-heptane was addedand stirred continuously for 30 minutes, the solid was precipitated andfiltered, and the filtrate was settled into layers, the organic phasewas collected, the water phase was extracted with toluene (15 mL×2times), the organic phases were combined and were concentrated to dryunder vacuum, a mixture was obtained. A few of the mixture was taken tobe separated to obtain three products, i.e. compounds XIIa, XIIIa, XIVa.

Compound XIIa: ¹H NMR (400 MHz, DMSO-d₆): 2.91-3.08 (m, 2H), 3.41 (td,1H, J=8.5, 2.1 Hz), 5.14 (d, 1H, J=2.0 Hz), 5.42 (d, 1H, J=13.1 Hz),5.46 (d, 1H, J=13.1 Hz), 6.17 (t, 1H, J=7.5 Hz), 7.13-7.26 (m, 6H), 7.35(d, 2H, J=8.5 Hz), 7.48-7.53 (m, 4H), 7.78 (t, 1H, J=8.0 Hz), 7.91 (t,1H, J=8.0 Hz), 8.21 (d, 1H, J=7.8 Hz), 8.44-8.47 (m, 2H), 8.51 (d, 1H,J=7.9 Hz), 8.56-8.59 (m, 1H), 8.76 (t, 1H, J=1.7 Hz); MS (m/z): 720[M+H]⁺, 742 [M+Na]⁺.

Compound XIIIa: ¹H NMR (400 MHz, DMSO-d₆): 2.85-2.98 (m, 2H), 3.30 (td,1H, J=8.5, 2.2 Hz), 4.92 (d, 1H, J=2.2 Hz), 5.40 (d, 1H, J=13.1 Hz),5.44 (d, 1H, J=13.1 Hz), 6.13 (t, 1H, J=7.5 Hz), 6.73 (d, 2H, J=8.5 Hz),7.12 (t, 2H, J=8.8 Hz), 7.16-7.21 (m, 6H), 7.47-7.50 (m, 2H), 7.79 (td,1H, J=7.7, 0.9 Hz), 8.21 (d, 1H, J=7.8 Hz), 8.45-8.47 (m, 2H), 9.52 (s,1H); MS (m/z): 571 [M+H]⁺.

Compound XIVa: ¹H NMR (400 MHz, CDCl₃): 0.28 (s, 9H), 2.97-3.01 (m, 2H),3.30 (td, 1H, J=7.9, 2.2 Hz), 4.72 (d, 1H, J=2.1 Hz), 5.37 (s, 2H), 6.07(t, 1H, J=7.6 Hz), 6.83 (d, 2H, J=8.5 Hz), 6.94 (t, 2H, J=8.6 Hz), 7.03(t, 2H, J=8.6 Hz), 7.20 (d, 2H, J=8.5 Hz), 7.24-7.28 (m, 2H), 7.35-7.38(m, 2H), 7.61 (t, 1H, J=8.0 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.38-8.41 (m,1H), 8.75 (t, 1H, J=1.7 Hz); MS (m/z): 643 [M+H]⁺.

Example 11: Preparation of(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxy-but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(I)

The mixture of the compounds of formula XIIa, XIIIa XIVa obtained inexample 10 and 90 mL acetone were added to a 250 mL reaction flask andwere dissolved under stirring, 23 mL (0.069 mol) aqueous lithiumhydroxide (3M) was added at room temperature and the reaction mixturewas reacted for 2˜3 hours under stirring and monitored by TLC until thespots of the raw material (compounds XIIa, XIIIa XIVa) disappeared.

The pH was adjusted to 4˜6 by 2M hydrochloric acid at room temperature,then the solution was concentrated under vacuum (30˜40° C.) to smallvolume, 100 mL ethyl acetate was added and stirred for 5 minutes, thesolution was settled into layers, the organic phase was collected, thewater phase was extracted with ethyl acetate (20 mL×2 times), theorganic phases were combined, aqueous sodium hydrogen carbonate (3.8 gsodium hydrogen carbonate dissolved in 40 mL water) was added andstirred for 30 minutes, the solution was settled into layers. The pH ofthe organic phase was adjusted to about 6 with 2M hydrochloric acid,settled into layers, the organic phase was washed 1 time with saturatedsalt water, dried over anhydrous sodium sulfate, filtered, the filtratewas concentrated to dry under reduced pressure. The residue was purifiedby column chromatography, recrystallized twice in the mixed solvent ofethyl acetate and n-heptane, filtered and dried to obtain 4.3 g compoundI (HPLC purity: 99.2%; yield: 44.7% calculated according to the feedingamount of compound XIa of example 10).

¹H NMR (400 MHz, DMSO-d₆): δ 2.71-2.84 (m, 2H), 3.23 (td, 1H, J=6.4, 2.0Hz), 4.40 (d, 2H, J=5.3 Hz), 4.87 (t, 1H, J=5.3 Hz), 4.94 (d, 1H, J=2.1Hz), 5.80 (t, 1H, J=7.5 Hz), 6.74 (d, 2H, J=8.5 Hz), 7.11-7.17 (m, 4H),7.20-7.25 (m, 4H), 7.39-7.43 (m, 2H), 9.50 (s, 1H); MS (m/z): 422 [M+H].

Example 12: Preparation of5-(4-fluorophenyl)-5-hydroxy-6-methoxy-6-oxo-hexanoic acid (IIIa)

60 Kg (337.9 mol) 6-methoxy-5,6-dioxo-hexanoic acid (compound IIa) and180 L tetrahydrofuran were added to a 2000 L reaction tank, the mixturewas protected under nitrogen and dissolved under stirring, thetemperature was decreased to −20° C.˜−10° C., 1M solution of4-fluorophenyl magnesium bromide in THF (800 L, 800 mol) was addedslowly drop by drop and the temperature was kept for the reaction for1˜2 hours after the addition. The reaction was monitored by TLC untilthe spots of the raw material (compound IIa) disappeared.

A solution of 25% aqueous ammonium chloride (30 Kg ammonium chloridedissolved in 90 L water) was added at the temperature of −20° C.˜0° C.and was stirred for 5 minutes, then the pH was adjusted to 3˜5 with 4Mhydrochloric acid at the temperature of 00° C. 30° C., then 400 Ln-heptane was added and stirred for 5 minutes, the solution was settledinto layers, the organic phase was collected, the water phase wasextracted with ethyl acetate (80 L 2 times), the organic phases werecombined and were washed 2 times with saturated salt water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure. The crude product was recrystallized in toluene,filtered and dried to obtain 45.6 Kg compound IIIa (HPLC purity: 70.8%;yield: 35.4%).

¹H NMR (DMSO-d₆): 1.33-1.43 (m, 2H), 1.89-1.96 (m, 1H), 1.99-2.04 (m,1H), 2.15 (t, 2H, J=7.6 Hz), 3.61 (s, 3H), 5.99 (s, 1H), 7.12-7.17 (m,2H), 7.47-7.51 (m, 2H), 12.02 (s, 1H); MS (m/z): 269 [M−H]⁻.

Example 13: Preparation of(Z)-5-(4-fluorophenyl)-6-methoxy-6-oxo-hex-4-enoic acid (IVa)

40.0 Kg (104.9 mol)5-(4-fluorophenyl)-5-hydroxy-6-methoxy-6-oxo-hexanoic acid (compoundIIIa) and 200 L dichloromethane were added to a 300 L reaction tank, themixture was dissolved under stirring and was protected by nitrogen, thetemperature was decreased, 31.2 Kg (110.6 mol) triflic anhydride wasadded at the temperature of 5˜15° C., then the reaction mixture wasrefluxed for 1˜2 hours and monitored by TLC until the spots of the rawmaterial (compound IIIa) disappeared.

The temperature was decreased, the reaction was stopped by adding 50 Lwater under the temperature of 5° C.˜15° C., stirred for 5 minutes andsettled into layers, the organic phase was collected, the water phasewas extracted with dichloromethane (40 L×2 times), the organic phaseswere combined and was washed 3 times with saturated salt water, driedover anhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure to obtain 25.2 Kg compound IVa (HPLC purity: 86.3%;yield: 82.3%).

¹H NMR (DMSO-d₆): 2.42 (t, 2H, J=7.3 Hz), 2.56 (q, 2H, J=7.3 Hz), 3.74(s, 3H), 6.27 (t, 1H, J=7.4 Hz), 7.18 (t, 2H, J=8.8 Hz), 7.32-7.36 (m,2H), 12.19 (s, 1H).

Example 14: Preparation of (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoicacid (V)

25.0 Kg (85.6 mol) (Z)-5-(4-fluorophenyl)-6-methoxy-6-oxo-hex-4-enoicacid (compound IVa) and 100 L toluene were added to a 500 L reactiontank, the mixture was dissolved under stirring and were protected bynitrogen, 13.0 Kg (100.8 mol) diisopropylethylamine was added, stirredfor 5 minutes. The temperature was decreased to −20° C.˜−15° C., 159.7Kg (281.2 mol) DIBAH toluene solution (25%) was added slowly drop bydrop and the temperature was kept for the reaction for 20˜40 minutesafter the addition. The reaction was monitored by TLC until the rawmaterial (compound IVa) was reacted completely.

The reaction mixture was added slowly drop by drop to aqueous sodiumhydroxide (30.2 Kg sodium hydroxide dissolved in 140 L water) below thetemperature of 15° C. and was stirred for 30 minutes. The solution wassettled into layers, the water phase was collected and extracted with 50L dichloromethane, the dichloromethane phase was discarded, the pH ofthe water phase was adjusted to 1˜2 below 2500 with 6M hydrochloricacid, 100 L ethyl acetate was added and stirred for 5 minutes. Thesolution was settled into layers, the organic phase was collected, thewater phase was extracted with ethyl acetate (40 L×3 times), the organicphases were combined and washed 2 times with saturated salt water, driedover anhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure. The crude product was recrystallized in toluene,filtered and dried to obtain 15.0 Kg compound V (HPLC purity: 92.1%;yield: 72.0%).

¹H NMR (DMSO-d₆): 2.38 (t, 2H, J=7.1 Hz), 2.47 (q, 2H, J=7.0 Hz), 4.34(s, 2H), 4.75 (br s, 1H), 5.78 (t, 1H, J=7.2 Hz), 7.13 (t, 2H, J=8.9Hz), 7.45-7.48 (m, 2H), 12.13 (br s, 1H).

Example 15: Preparation of(Z)-5-(4-fluorophenyl)-6-(3-nitrobenzoyloxy)hex-4-enoic acid (VIa)

15.0 Kg (61.7 mol) (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid(compound V) and 50 L N, N-dimethylacetamide were added to a 300 Lreaction tank, the mixture was dissolved under stirring and wereprotected by nitrogen. The temperature was decreased to −5° C.˜5° C.,24.9 Kg (134.2 mol) 3-nitrobenzoyl chloride was added and thetemperature was kept for the reaction for 5˜6 hours. The reaction wasmonitored by TLC until the spots of the raw material (compound V)disappeared.

Aqueous pyridine was added (10.4 Kg pyridine dissolved in 30 L water) atthe temperature of 0° C.˜10° C. and was stirred for 30 minutes. Thenaqueous imidazole (18.0 Kg imidazole dissolved in 50 L water) was addedat the temperature of 0° C.˜10° C. and was stirred for 1˜2 hours, then100 L ethyl acetate was added and was stirred for 5 minutes. Thesolution was settled into layers, the organic phase was collected, thewater phase was extracted with ethyl acetate (20 L×3 times), the organicphases were combined and were washed with water, the pH was adjusted to3˜5 with 2M hydrochloric acid, washed 1 time with saturated salt water,dried over anhydrous sodium sulfate, filtered and evaporated to drynessunder reduced pressure to obtain 20.2 Kg compound VIa (HPLC purity:85.6%; yield: 75.2%).

¹H NMR (DMSO-d₆): 2.45 (t, 2H, J=7.1 Hz), 2.59 (q, 2H, J=7.3 Hz), 5.36(s, 2H), 6.09 (t, 1H, J=7.4 Hz), 7.18 (t, 2H, J=8.8 Hz), 7.51-7.54 (m,2H), 7.80 (t, 1H, J=7.8 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.46-8.48 (m, 2H),12.17 (s, 1H).

Example 16: Preparation of[(Z)-2-(4-fluorophenyl)-6-oxo-6-[(4S)-2-oxo-4-phenyl-oxazolidin-3-yl]hex-2-enyl]3-nitrobenzoate(VIIIa)

20.0 Kg (45.9 mol)(Z)-5-(4-fluorophenyl)-6-(3-nitrobenzoyloxy)-hex-4-enoic acid (compoundVIa) and 100 L dichloromethane were added to a 300 L reaction tank, themixture was dissolved under stirring and were protected by nitrogen. 6.8Kg (56.4 mol) pivaloyl chloride was added. At room temperature, 12.0 Kg(118.8 mol) triethylamine was added slowly drop by drop, the reactionmixture was reacted at room temperature for 3˜4 hours after theaddition, then 6.0 Kg (36.8 mol) (S)-4-phenyl-2-oxazolidinone (compoundVII) and 1.7 Kg (13.9 mol) 4-dimethylaminopyridine were added andreacted at room temperature for 4˜5 hours. The reaction was monitored byTLC until the spots of the raw material (compound VIa) disappeared.

The pH was adjusted to 4˜6 with 2M hydrochloric acid, the solution wassettled into layers, the organic phase was collected, and the waterphase was extracted with dichloromethane (25 L×2 time), the organicphases were combined, aqueous imidazole (8.6 Kg imidazole dissolved in30 L water) was added and stirred for 2˜3 hours, then was washed 1 timewith saturated salt water, dried over anhydrous sodium sulfate, filteredand evaporated to dryness under reduced pressure. The crude product wasrecrystallized in toluene, filtered and dried to obtain 15.2 Kg compoundVIIIa (HPLC purity: 91.7%; yield: 58.6%).

¹H NMR (DMSO-d₆): 2.59 (q, 2H, J=7.2 Hz), 3.00-3.18 (m, 2H), 4.15 (dd,1H, J=8.8, 3.6 Hz), 4.72 (t, 1H, J=8.7 Hz), 5.29 (d, 1H, J=13.2 Hz),5.32 (d, 1H, J=13.2 Hz), 5.45 (dd, 1H, J=8.6, 3.6 Hz), 6.05 (t, 1H,J=7.5 Hz), 7.17 (t, 2H, J=8.9 Hz), 7.26-7.36 (m, 5H), 7.46-7.50 (m, 2H),7.76-7.80 (m, 1H), 8.19-8.21 (m, 1H), 8.45-8.47 (m, 2H).

Example 17: Preparation of[(Z,5R)-5-[(S)-(4-fluoroanilino)-[4-(3-nitrobenzoyl)oxyphenyl]methyl]-2-(4-fluorophenyl)-6-oxo-6-[(4S)-2-oxo-4-phenyl-oxazolidin-3-yl]hex-2-enyl]3-nitrobenzoate(XIa)

60 L dichloromethane and 6.0 Kg (31.6 mol) titanium tetrachloride wereadded to a 100 L reaction tank and were protected under nitrogen,stirred, the temperature was decreased, 3.0 Kg (10.6 mol) tetraisopropyltitanate was added at the temperature of −5° C.˜0° C., then stirred for30 minutes at the temperature of −5° C.˜0° C. to obtain titaniumreagent. 15.0 Kg (26.6 mol) compound of formula VIIIa, 10.6 Kg (29.1mol) imine of formula IXa and 220 L dichloromethane were added to a 500L reaction tank and were dissolved under stirring, 8.3 Kg (64.3 mol)diisopropylethylamine was added and stirred for 10 minutes, thetemperature was decreased, the titanium reagent was added slowly drop bydrop at the temperature of −25° C.˜−20° C., the temperature was kept toreact for 1˜2 hours after the addition. The reaction was monitored byHPLC until the content of the raw material (compound VIIIa) was <5%.

18 L acetic acid was added at the temperature of −25° C.˜−20° C., thenwas stirred for 5 minutes; 90 L sulfuric acid (2M) was added drop bydrop below 10° C., then was stirred for 10 minutes. The solution wassettled into layers, the organic phase was collected, and the waterphase was extracted with 30 L dichloromethane. The organic phases werecombined and washed 3 times with saturated salt water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness underreduced pressure. The crude product was recrystallized in toluene,filtered and dried to obtain 12.3 Kg compound XIa (HPLC purity: 92.1%;yield: 48.4%).

¹H NMR (DMSO-d₆): 2.38-2.45 (m, 1H), 2.56-2.64 (m, 1H), 4.11 (dd, 1H,J=8.8, 4.7 Hz), 4.62-4.75 (m, 3H), 5.15 (s, 2H), 5.51 (dd, 1H, J=8.5,4.6 Hz), 5.98 (t, 1H, J=7.4 Hz), 6.34 (d, 1H, J=9.8 Hz), 6.58-6.62 (m,2H), 6.80 (t, 2H, J=8.9 Hz), 7.13-7.28 (m, 9H), 7.45-7.48 (m, 2H), 7.54(d, 2H, J=8.5 Hz), 7.79 (t, 1H, J=7.9 Hz), 7.91 (t, 1H, J=8.0 Hz), 8.18(d, 1H, J=7.8 Hz), 8.43-8.49 (m, 3H), 8.57-8.60 (m, 1H), 8.74 (t, 1H,J=1.8 Hz); MS (m/z): 883 [M+H]⁺.

Example 18: Preparation of(3R,4S)-4-[4-(3-nitrobenzoyloxy)phenyl]-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(XIIa),(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(XIIIa),(3R,4S)-4-(4-trimethylsilyloxyphenyl)-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(XIVa)

12.0 Kg (12.5 mol) compound of formula XIa and 120 L toluene were addedto a 300 L reaction tank and were stirred and heated, 10.2 Kg (50.0 mol)N,O-bis(trimethylsilyl)acetamide (BSA) was added at 50° C.˜60° C.,reacted for 2˜3 hours at said temperature; then 0.6 Kg (1.9 mol)tetrabutylammonium fluoride trihydrate was added and the temperature waskept for the reaction for 2˜3 hours. The reaction was monitored by HPLCuntil the content of the raw material (compound XIa) was <1.0%.

The temperature was decreased, 30 L ice water was added drop by dropbelow 25° C., the solution was stirred for 10 minutes, then 100 Ln-heptane was added and stirred for 30 minutes, the solids wereprecipitated and filtered, the filtrate was settled into layers, theorganic phase was collected, and the water phase was extracted withtoluene (10 L×2 times). The organic phases were combined and wereconcentrated to dry under vacuum to obtain a mixture. A few of themixture was taken to be separated to obtain three products, i.e.compound XIIa, XIIIa, XIVa.

Compound XIIa: ¹H NMR (400 MHz, DMSO-d₆): 2.91-3.08 (m, 2H), 3.41 (td,1H, J=8.5, 2.1 Hz), 5.14 (d, 1H, J=2.0 Hz), 5.42 (d, 1H, J=13.1 Hz),5.46 (d, 1H, J=13.1 Hz), 6.17 (t, 1H, J=7.5 Hz), 7.13-7.26 (m, 6H), 7.35(d, 2H, J=8.5 Hz), 7.48-7.53 (m, 4H), 7.78 (t, 1H, J=8.0 Hz), 7.91 (t,1H, J=8.0 Hz), 8.21 (d, 1H, J=7.8 Hz), 8.44-8.47 (m, 2H), 8.51 (d, 1H,J=7.9 Hz), 8.56-8.59 (m, 1H), 8.76 (t, 1H, J=1.7 Hz); MS (m/z): 720[M+H]⁺, 742 [M+Na]⁺.

Compound XIIIa: ¹H NMR (400 MHz, DMSO-d₆): 2.85-2.98 (m, 2H), 3.30 (td,1H, J=8.5, 2.2 Hz), 4.92 (d, 1H, J=2.2 Hz), 5.40 (d, 1H, J=13.1 Hz),5.44 (d, 1H, J=13.1 Hz), 6.13 (t, 1H, J=7.5 Hz), 6.73 (d, 2H, J=8.5 Hz),7.12 (t, 2H, J=8.8 Hz), 7.16-7.21 (m, 6H), 7.47-7.50 (m, 2H), 7.79 (td,1H, J=7.7, 0.9 Hz), 8.21 (d, 1H, J=7.8 Hz), 8.45-8.47 (m, 2H), 9.52 (s,1H); MS (m/z): 571 [M+H]⁺.

Compound XIVa: ¹H NMR (400 MHz, CDCl₃): 0.28 (s, 9H), 2.97-3.01 (m, 2H),3.30 (td, 1H, J=7.9, 2.2 Hz), 4.72 (d, 1H, J=2.1 Hz), 5.37 (s, 2H), 6.07(t, 1H, J=7.6 Hz), 6.83 (d, 2H, J=8.5 Hz), 6.94 (t, 2H, J=8.6 Hz), 7.03(t, 2H, J=8.6 Hz), 7.20 (d, 2H, J=8.5 Hz), 7.24-7.28 (m, 2H), 7.35-7.38(m, 2H), 7.61 (t, 1H, J=8.0 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.38-8.41 (m,1H), 8.75 (t, 1H, J=1.7 Hz); MS (m/z): 643 [M+H]⁺.

Example 19: Preparation of(3R,4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybut-2(Z)-enyl]-1-(4-fluorophenyl)azetidin-2-one(I)

The mixture of compounds XIIa, XIIIa, XIVa obtained in example 18 and 50L acetone were added to a 100 L reaction tank and were dissolved understirring, 13 L (39.0 mol) aqueous lithium hydroxide (3M) was added atroom temperature and was reacted for 0.5˜1 hour under stirring. Thereaction was monitored by TLC until the spots of the raw material(compound XIIa, XIIIa, XIVa) disappeared.

The pH was adjusted to 4˜6 with 2M hydrochloric acid at roomtemperature, then the solution was concentrated under vacuum (at 30°C.˜40° C.) to small volume, 60 L ethyl acetate was added and stirred for5 minutes, then the solution was settled into layers, the organic phasewas collected, the water phase was extracted with ethyl acetate (10 L 2times). The organic phases were combined, aqueous sodium bicarbonate(2.0 Kg sodium bicarbonate dissolved in 20 L water) was added, stirredfor 30 minutes, the solution was settled into layers, the pH of theorganic phase was adjusted to about 6 with 2M hydrochloric acid, thesolution was settled into layers, the organic phase was washed 1 timewith saturated salt water, dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated to dry under reduced pressure.The residue was purified by column chromatography, crystallized twice inthe mixed solvent of ethyl acetate and n-heptane, filtered and dried toobtain 2.1 Kg compound I (HPLC purity: 98.9%; yield: 39.4% calculatedaccording to the feeding amount of compound XIa of example 18).

¹H NMR (400 MHz, DMSO-d₆): δ 2.71-2.84 (m, 2H), 3.23 (td, 1H, J=6.4, 2.0Hz), 4.40 (d, 2H, J=5.3 Hz), 4.87 (t, 1H, J=5.3 Hz), 4.94 (d, 1H, J=2.1Hz), 5.80 (t, 1H, J=7.5 Hz), 6.74 (d, 2H, J=8.5 Hz), 7.11-7.17 (m, 4H),7.20-7.25 (m, 4H), 7.39-7.43 (m, 2H), 9.50 (s, 1H); MS (m/z): 422 [M+H].

The invention claimed is:
 1. A method for preparing the compoundrepresented by formula (I),

comprising the following steps: (a) reacting the compound of formula Vwith a hydroxyl protectant to obtain the compound of formula VI:

wherein R² is an alcoholic hydroxyl protecting group; (b) converting thecarboxylic acid of formula VI into mixed anhydride or acyl halide, thenreacting with (S)-4-phenyl-2-oxazolidone of formula VII which is used asa chiral auxiliary to obtain a derivative of oxazolidone of formulaVIII:

wherein the carboxylic acid of formular VI is reacted with an acylatingagent to produce mixed anhydride; or the carboxylic acid of formula VIis reacted with phosphorus trihalide, phosphorus pentahalide,dichlorosulfane (SOCl₂), oxalyl chloride((COCl)₂) or phosgene (COCl₂) toproduce acyl halide; X is chlorine or bromine; or the above step (a) andstep (b) can be carried out in one step, the compound of formula VIIIcan be prepared from the compound of formula V through a one-pot methodwith the following specific steps: (ab) reacting the compound of formulaV with a hydroxyl protecting agent to obtain the compound of formula VI,further converting the carboxylic acid of formula VI into mixedanhydride or acyl halide without separation and purification, thenreacting with (S)-4-phenyl-2-oxazolidone of formula VII which is used asa chiral auxiliary to obtain a derivative of oxazolidone of formulaVIII:

wherein R² is an alcoholic hydroxyl protecting group; and wherein thecarboxylic acid of formula VI is reacted with an acylating agent toproduce mixed anhydride; or the carboxylic acid of formula VI is reactedwith phosphorus trihalide, phosphorus pentahalide, dichlorosulfane(SOCl₂), oxalyl chloride((COCl)₂) or phosgene (COCl₂) to produce acylhalide; X is chlorine or bromine; (c) under the presence of Lewis acids(titanium tetrachloride (TiCl₄) and tetraisopropyl titanate) andtertiary amine, reacting the oxazolidone derivative of formula VIII withan imine of formula IX to obtain an addition product of formula XI:

wherein R² and R³ are all hydroxyl protecting groups, which can be thesame or different; (d) cyclizing the addition product of formula XI withN,O-bis(trimethylsilyl)acetamide (BSA) and tetrabutylammonium fluoride(TBAF) to obtain the β-lactams of formula XII, XIII and XIV:

and (e) obtaining the compound of formula (I) via the deprotection ofthe mixture of the compounds of formula XII, XIII and XIV obtained instep (d):


2. The method according to claim 1, further comprising the followingstep before step (a) or (ab): (a′) carrying out a Grignard additionselectively to the ketone of formula II with 4-fluorophenyl magnesiumhalide to obtain the tertiary alcohol of formula III:

wherein, R¹ is C₁-C₆ alkyl; X is a halogen; (a″) under the action of adehydrating agent, the tertiary alcohol of formula III is dehydratedstereoselectively to obtain the (Z)-α,β-unsaturated ester of formula IV:

wherein R¹ is C₁-C₆ alkyl; and (a″′) under the action of a reducingagent, the ester of formula IV is reduced selectively to the alcohol offormula V:

wherein R¹ is C₁-C₆ alkyl.
 3. The method according to claim 1, whereinin step (a) or (ab), the alcoholic hydroxyl protecting group R² isselected from acetyl, or benzoyl that is unsubstituted or substituted byhalogen, alkyl or nitro; the molar ratio of the compound V to thehydroxyl protecting agent in step (a) is 1:1.0˜3.0, or the molar ratioof the compound V to the hydroxyl protecting agent in step (ab) is1:1.0˜3.0; and the solvent of the reaction in step (a) or the solvent ofthe reaction of synthesizing compound of formula VI from the compound offormula V in step (ab) is selected from N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO),1,3-dimethylpropyleneurea (DMPU) or hexamethylphosphoramide (HMPA). 4.The method according to claim 1, wherein in step (b) or step (ab), theacylating agent used for forming the mixed anhydride is selected frompivaloyl chloride, 3-nitrobenzoyl chloride or isobutyl chloroformate;and in step (b), the molar ratio of the compound of formula VI to theacylating agent is 1:1.0˜2.0, preferably, and the molar ratio of thecompound of formula VI to (S)-4-phenyl-2-oxazolidone is 1:0.5˜1.5; or instep (ab), the molar ratio of the compound of formula V to the acylatingagent is 1:1.0˜2.0, and the molar ratio of the compound of formula V to(S)-4-phenyl-2-oxazolidone is 1:0.5˜1.5.
 5. The method according toclaim 1, wherein in step (c), R² is defined as in claim 3; R³ isselected from acetyl, or benzoyl that is unsubstituted or substituted byhalogen, alkyl or nitro; the tertiary amine is diisopropylethylamine(DIPEA); the molar ratio of the compound of formula VIII to the imine offormula IX is 1:1.0˜2.0; the reaction temperature is controlled between−90° C.˜0° C.; and after the completion of the reaction in the step (c),a post-processing quenching reaction is carried out, and alcohols, acidsor mixed liquids of acids diluted by organic solvents are used in thepost-processing quenching reaction; wherein the alcohols are selectedfrom methanol, ethanol, propanol, isopropanol, or tertiary butanol;wherein the acids are inorganic acids or organic acids, wherein theinorganic acids are selected from the group consisting of hydrochloricacid, sulfuric acid, nitric acid, and hydrobromic acid, and the organicacids are selected from the group consisting of formic acid, aceticacid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, benzoic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, maleic acid and tartaric acid. 6.The method according to claim 1, wherein in step (d), the solvent of thereaction is selected from acetonitrile or toluene; the molar ratio ofthe compound of formula XI to N,O-bis(trimethylsilyl)acetamide (BSA) is1:1.0˜5.0; and the molar ratio of the compound of formula XI totetrabutylammonium fluoride trihydrate (TBAF) is 1:0.1˜0.5.
 7. Themethod according to claim 1, wherein in step (e), the solvent used forthe deprotection of the mixture of the compounds of formula XII, XIIIand XIV is selected from tetrahydrofuran or acetone; the alkali isselected from aqueous lithium hydroxide, aqueous sodium hydroxide oraqueous potassium hydroxide; and the molar ratio of the alkali to thecompound of formula XI in step (d) is 3.0˜5.0:1.
 8. The method accordingto claim 2, wherein in step (a′), the molar ratio of the compound offormula II to 4-fluorophenyl magnesium halide is 1:1.0˜5.0,4-fluorophenyl magnesium halide is 4-fluorophenyl magnesium bromide, andthe reaction temperature is controlled between −78° C.˜−5° C.; in step(a″), the molar ratio of the compound of formula III to the dehydratingagent is 1:1.0˜3.0, the dehydrating agent is selected from concentratedsulfuric acid, p-toluenesulfonic acid, phosphoric acid, triflicanhydride or methanesulfonic acid, and the solvent of the reaction isselected from dichloromethane or toluene; and in step (a″′), the molarratio of the compound of formula IV to the reducing agent is 1:2.5˜5.0;the reducing agent is diisobutylaluminium hydride (DIBAH), and thesolvent of the reaction is selected from dichloromethane,tetrahydrofuran, toluene or dioxane.
 9. The method according to claim 2,wherein R¹ is methyl, ethyl or isopropyl; and X is chlorine, bromine oriodine.
 10. The method according to claim 3, wherein the alcoholichydroxyl protecting group R² is nitro-substituted benzoyl; the molarratio of the compound V to the hydroxyl protecting agent in step (a) is1:1.2˜2.3; or the molar ratio of the compound V to the hydroxylprotecting agent in step (ab) is 1:1.0˜1.5; and the solvent of thereaction in step (a) or the solvent of the reaction of synthesizingcompound of formula VI from the compound of formula V in step (ab) isN,N-dimethylacetamide (DMA).
 11. The method according to claim 10,wherein the alcoholic hydroxyl protecting group R² is 3-nitrobenzoyl.12. The method according to claim 4, wherein in step (b) or step (ab),the acylating agent used for forming the mixed anhydride is pivaloylchloride or 3-nitrobenzoyl chloride; and in step (b), the molar ratio ofthe compound of formula VI to the acylating agent is 1:1.1˜1.6, and themolar ratio of the compound of formula VI to (S)-4-phenyl-2-oxazolidoneis 1:0.8˜1.1; or in step (ab), the molar ratio of the compound offormula V to the acylating agent is 1:1.0˜1.5, and the molar ratio ofthe compound of formula V to (S)-4-phenyl-2-oxazolidone is 1:0.7˜1.1.13. The method according to claim 5, wherein R² or R³ isnitro-substituted benzoyl; the molar ratio of the compound of formulaVIII to the imine of formula IX is 1:1.0˜1.2; the reaction temperatureis controlled between −80° C.˜−20° C.; the alcohol used in thepost-processing quenching reaction after the completion of the reactionin the step (c) is isopropanol; and the acids used in thepost-processing quenching reaction after the completion of the reactionin the step (c) are the organic acids, wherein the organic acids areselected from the group consisting of formic acid, acetic acid,trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonicacid, benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, citricacid, maleic acid and tartaric acid.
 14. The method according to claim13, wherein R² or R³ is 3-nitrobenzoyl; and the acid used in thepost-processing quenching reaction after the completion of the reactionin the step (c) is acetic acid or trifluoroacetic acid.
 15. The methodaccording to claim 6, wherein in step (d), the solvent of the reactionis toluene; the molar ratio of the compound of formula XI toN,O-bis(trimethylsilyl)acetamide (BSA) is 1:2.0˜4.0; and the molar ratioof the compound of formula XI to tetrabutylammonium fluoride trihydrate(TBAF) is 1:0.1˜0.3.
 16. The method according to claim 7, wherein instep (e), the solvent used for the deprotection of the mixture of thecompounds of formula XII, XIII and XIV is acetone; and the alkali isaqueous lithium hydroxide.
 17. The method according to claim 8, whereinin step (a′), the molar ratio of the compound of formula II to4-fluorophenyl magnesium halide is 1:1.1˜3.0, and the reactiontemperature is controlled between −50° C.˜−10° C.; in step (a″), themolar ratio of the compound of formula III to the dehydrating agent is1:1.0˜1.5, the dehydrating agent is triflic anhydride, and the solventof the reaction is dichloromethane; and in step (a″′), the molar ratioof the compound of formula IV to the reducing agent is 1:3.0˜4.0; andthe solvent of the reaction is toluene.